1. Field of the Invention (Technical Field):
The present invention relates to metallopeptides, and metallopeptide combinatorial libraries specific for opioid receptors, and which are agonist, antagonist or mixed agonist-antagonists, including methods for the use and making of the same.
2. Background Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Opioid Receptors and Use of Opioids in Medicine. Morphine, related narcotics and other synthetic non-peptide opioids have been used through all of recorded history to alleviate pain. However, persistent use of these opiates in pain management is associated with several serious drawbacks such as addiction, depression of cardiovascular and respiratory functions and acute constipation. Recent strides in opiate research have established that most of these ill effects of narcotics are mediated through the mu (μ) opioid receptors. The delta (δ)-receptor, on the other hand, mediates antinociception without these serious side effects. (See, for example, Dhawan B N, Cesselin F, Raghubir R, Reisine T, Bradley P B, Portoghese P S, Hamon M. International union of pharmacology XII. Classification of opioid receptors. Pharmacol. Rev. 48: 567–592, 1996; Fundytus M E, Schiller P W, Shipiro M et al. Attenuation of morphine tolerance and dependence with highly selective delta opioid receptor antagonist TIPP. Eur J Pharmacol 286:105–108, 1995; Jiang Q, Mosberg H I, Porreca F. Selective modulation of morphine antinociception, but not development of tolerance, by delta receptor agonist. Eur J Pharmacol 186:137–141, 1990). Major research effort in past several years has been focused on developing potent and selective δ receptor agonists for clinical use in pain management. See, for example, U.S. Pat. No. 5,872,097.
The μ-, δ-, and kappa (κ) opiate receptors are all G protein-coupled, 7-transmembrane receptors. All these receptors can bind various peptide analogs containing a common opiate pharmacophore, Tyr-[X]n-Phe (message sequence). All the endogenous and naturally occurring opioid peptides (such as enkephalins, endorphins, dynorphins, casomorphins, deltorphins and dermorphin) display this pharmacophore. Excellent progress has been made in developing a variety of potent and receptor-selective opioid peptide analogs (See, for example, Schiller P W, Weltrowska G, et al. Subtleties of structure-agonist versus antagonist relationships of opioid peptides and peptidomimetics. J Recept Signal Transduct Res 19:573–88, 1999; Hruby V J, Bartosz-Bechowski H, Davis P et al. Cyclic enkephalin analogues with exceptional potency and selectivity for delta-opioid receptors. J Med Chem 40:3957–62, 1997), peptidomimetics and non-peptide molecules (See, for example, Liao S, Alfaro-Lopaz J, Shederovich M D, et al. De novo design, synthesis and biological activity of high affinity and selective non-peptide agonist of the delta-opioid receptors. J Med Chem 41:4767–4776, 1998; Gao P, Larson D L, Portoghese. Synthesis of 7-arylmorphinans. Probing the address requirements for selectivity at opioid delta receptors. J Med Chem 41:3091–3098, 1998). Several of these ligands are highly selective and potent for the δ opiate receptor and produce antinociception under strict experimental conditions.
Besides potency and receptor selectivity, there are two other requisites for a clinically useable opiate receptor-based analgesic for pain management. The drug must be able to cross the blood-brain-barrier (BBB) to reach and interact with its brain receptor, and it must be orally active. Most prior art peptide analogs and peptidomimetics are not systemically bioavailable, either in terms of crossing the BBB or oral absorption, which has precluded their further clinical development as analgesics. Many non-peptide δ ligands are systemically active in producing analgesia, and thus capable of crossing the BBB, but are not active upon oral administration. There is a clear need for potent and selective δ opiate receptor agonists that are orally active in producing antinociception. In general, there is a need for selective opiate receptor agonists and antagonists to the μ-, δ, and κ-opiate receptors.
In general, prior research has been conducted on both peptide and non-peptide opioids. For example, U.S. Pat. No. 5,965,701 discloses receptor-specific peptides, while U.S. Pat. Nos. 6,028,063 and 6,057,357 disclose non-peptide κ opioid agonists and PCT/US99/18021 discloses a κ receptor antagonist. U.S. Pat. Nos. 5,885,958 and 5,919,897 and PCT/US99/13638 disclose μ-opioid receptor-specific agents which are peptides, peptidomimetics or other small molecules, displaying both agonist and antagonist activity.
Peptide Libraries and Combinatorial Chemistry. U.S. Pat. No. 6,027,711 and PCT/US00/16396 teach combinatorial chemistry techniques, including a summary of methods employed as tools for rapid drug discovery. A library of peptides and other small molecules, with its enormous pool of structurally diverse molecules, is well suited for both lead generation as well as lead optimization. Libraries of a variety of molecular species have been described in literature and screened for drug discovery. These molecular species include peptides, peptoids, peptidomimetics, oligonucleotides, benzodiazepines, and other libraries of small organic molecules.
Various approaches used to construct a library of structurally diverse chemical compounds include chemical synthesis and genetic engineering methods. Chemically synthesized libraries can be either soluble (a mixture of various compounds in a solution) or solid (compounds synthesized on a solid surface). Libraries produced by genetic engineering tools are largely composed of peptide molecules, and are similar to solid-phase libraries in the sense that the peptide sequences are displayed or attached on the surface of plasmids, bacteriophages or bacteria used for their production.